A Seven-Gene Signature Aggregates a Subgroup of Stage II Colon Cancers with Stage III

Laibe, Sophy; Lagarde, Arnaud; Ferrari, Anthony; Monges, Geneviève; Birnbaum, Daniel; Olschwang, Sylviane

doi:10.1089/omi.2012.0039

Cited by 72 publications

(41 citation statements)

References 26 publications

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“…S6 in Supplementary Appendix 1). 12,13,26,27 Patients were stratified into negative-to-low (negative) and high (positive) subgroups with regard to CDX2 and ALCAM gene-expression levels with the use of the StepMiner algorithm, implemented within the Hegemon 21 software (Fig. S7 through S10 in Supplementary Appendix 1).…”

Section: Methodsmentioning

confidence: 99%

CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer

et al. 2016

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Background The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice. Methods We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III colon cancer, the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy. Results The transcription factor CDX2 ranked first in our screening test. A group of 87 of 2115 tumor samples (4.1%) lacked CDX2 expression. In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P = 0.002). In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein–negative colon cancers than among the 276 (87.9%) with CDX2 protein–positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P = 0.003). In both these groups, these findings were independent of the patient's age, sex, and tumor stage and grade. Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P = 0.003) and in the validation data set (51% among 15 patients with CDX2-negative tumors vs. 80% among 106 patients with CDX2-positive tumors, P = 0.004). In a pooled database of all patient cohorts, the rate of 5-year disease-free survival was higher among 23 patients with stage II CDX2-negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy (91% vs. 56%, P = 0.006). Conclusions Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.)

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Section: Methodsmentioning

confidence: 99%

CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer

et al. 2016

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“…This cohort included gene expression data from four publicly available NCBI-GEO data-series (GSE14333, GSE17538, GSE31595, GSE37892)(74–77), and contained information on 466 unique primary colon carcinoma samples, collected from patients at various clinical stages (AJCC Stage I-IV/Duke’s Stage A-D) by five independent institutions: 1) the H. Lee Moffit Cancer Center in Tampa, Florida, USA; 2) the Vanderbilt Medical Center in Nashville, Tennessee, USA; 3) the Royal Melbourne Hospital in Melbourne, Australia; 4) the Institut PaoliCalmette in Marseille, France; 5) the Roskilde Hospital in Copenhagen, Denmark. All 466 samples contained in this subset were cross-checked to exclude the presence of redundancies/duplicates.…”

Section: Methodsmentioning

confidence: 99%

Convergence of Wnt, growth factor, and heterotrimeric G protein signals on the guanine nucleotide exchange factor Daple

et al. 2018

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Cellular proliferation, differentiation, and morphogenesis are shaped by multiple signaling cascades; their concurrent dysregulation plays an integral role in cancer progression and is a common feature of many malignancies. Three such cascades that contribute to the oncogenic potential are those mediated by Wnt and Frizzled (FZD), growth factor receptor tyrosine kinases (RTKs), and trimeric G proteins and GPCRs. Daple is a Dishevelled (Dvl)- and FZD-binding protein and a guanine-nucleotide exchange factor (GEF) for the trimeric G protein, Gαi. Daple enhances β-catenin-independent Wnt signaling through its ability to activate the pathway downstream of the Wnt5/FZD7 pathway. Here we identified that Daple is a substrate of multiple RTKs and non-RTKs, and hence, a point of convergence for all three cascades. We show that phosphorylation by both RTKs and non-RTKs near the Dvl-binding motif in Daple dissociated Daple:Dvl complexes and augmented the ability of Daple to bind and activate Gαi which potentiated β-catenin-independent Wnt signals and triggered epithelial-mesenchymal transition (EMT) in a manner similar to that triggered by Wnt5A/FZD. Although Daple acts as a tumor suppressor in the healthy colon, but concurrent upregulation of Daple and epidermal growth factor receptor (EGFR) in colorectal tumors from patients was associated with poor prognosis. We conclude that Daple-dependent activation of Gαi and enhancement of β-catenin-independent Wnt signals is not just triggered by Wnt5a/FZD to suppress tumorigenesis, but also is hijacked by growth factor-RTKs to stoke tumor progression. Thus, this work defines a crosstalk paradigm amongst growth factor RTKs, trimeric G-proteins, and Wnt/FZD in cancer biology.

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“…These data suggest that UBA7 per se is not an initiating oncogene in human CRC. To address whether UBE1L has any regulatory function in human CRC, we used two recently published datasets (40,41) to compare clinical outcomes in groups of CRC patients with low or high UBA7 expression. Results from the two datasets revealed that higher expression levels of the UBE1L gene UBA7 correlated significantly with worse survival (Fig.…”

Section: Protein Isgylation Is Correlated With Patient Survival In Humentioning

confidence: 99%

Type I IFN induces protein ISGylation to enhance cytokine expression and augments colonic inflammation

Fan

Miyauchi-Ishida

Arimoto

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Type I IFNs have broad activity in tissue inflammation and malignant progression that depends on the expression of IFN-stimulated genes (ISGs). ISG15, one such ISG, can form covalent conjugates to many cellular proteins, a process termed "protein ISGylation." Although type I IFNs are involved in multiple inflammatory disorders, the role of protein ISGylation during inflammation has not been evaluated. Here we report that protein ISGylation exacerbates intestinal inflammation and colitis-associated colon cancer in mice. Mechanistically, we demonstrate that protein ISGylation negatively regulates the ubiquitin-proteasome system, leading to increased production of IFN-induced reactive oxygen species (ROS). The increased cellular ROS then enhances LPS-induced activation of p38 MAP kinase and the expression of inflammation-related cytokines in macrophages. Thus our studies reveal a regulatory role for protein ISGylation in colonic inflammation and its related malignant progression, indicating that targeting ubiquitin-activating enzyme E1 homolog has therapeutic potential in treating inflammatory diseases.

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A Seven-Gene Signature Aggregates a Subgroup of Stage II Colon Cancers with Stage III

Cited by 72 publications

References 26 publications

CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer

CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer

Convergence of Wnt, growth factor, and heterotrimeric G protein signals on the guanine nucleotide exchange factor Daple

Type I IFN induces protein ISGylation to enhance cytokine expression and augments colonic inflammation

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